About Epigenetic

1. Epigenetics
Mozhdeh rastegari
IN the name of GOD

2. Introduction

3. • epigenetics = on top of genetics
• chemical modifications of chromosomal DNA and/or
structures that change the pattern of gene expression without
altering the DNA sequence.
• Epigenetic modifications turn genes on or off which prevents
or allows the gene to make a protein.
Epigenetics

4. Epigenetics
• all cells contain the same genes, BUT
• gene expression patterns are different in different cells

5. Epigenome is changeable
• at different times in life different genes are
needed cells are constantly listening for
signals to change what they are doing signals
come from inside the cell, neighbouring cells
or the environment.

6. Genetics vs. Epigenetics

7. Epigenetics is based on
different mechanisms
1. Histone modification
2. DNA Methylation
3. Non coding RNAs

8. • Numerous post-translational
histone modifications
• Refer to chemical alterations taking place on the N -tails of nucleosomal
histones.
• These chemical modifications affect chromatin architecture leading to open
(active) or closed (repressive) chromatin states which regulate
transcriptional activity and are inherited by daughter cells.

9. Histone modifications
determine function
• Epigenetic marks – small chemical tags that sit on top of chromatin and help instruct it
whether to open or to compact.

10. Histone acetylation
• Acetylation of the lysine residues at the N terminus of histons removes positive charges, thereby reducing the
affinity between histones and DNA. This makes RNA polymerase and transcription factors easier to access the
promoter region. Therefore, in most cases, histone acetylation enhances transcription while histone
deacetylation represses transcription.
• Histone acetylation is catalyzed by histone acetyltransferases (HATs) and histone deacetylation is catalyzed
by histone deacetylases (denoted by HDs or HDACs). Several different forms of HATs and HDs have been
identified. Among them, CBP/p300 is probably the most important, since it can interact with numerous
transcription regulators.

11. Histone acetylation Mechanism
• Acetylation of H3 or H4 leads to unfolding and increased
accessibility o fchromatin to enable transcription.
• Histones are acetylated by HAT(histoneacetylases) which are
parts of many chromatin remodeling and transcription complexes.

12. Mechanism of histone acetylation

13. Histone Methylation
• Unlike acetylation, histone methylation does not alter the charge of the modified residues
and it is therefore less likely to directly alter nucleosomal interactions required for
chromatin folding . This probably explains why histone methylation can either repressor
activate transcription depending on location.
• Arginine methylation of histone H3 and H4 promotes transcriptional activation , whereas
lysine methylation of histone H3 and H4 is implicated in both transcriptional activation
and repression , depending on the methylation site . In addition , lysine residues can be
methylated in the form of mono-,di-,or tri- methylation , providing further functional
diversity to each site of lysine methylation .For example, tri-methylation on K4 of Histone
H3 (H3K4me3) is generally associated with transcriptional activation,whereas tri-
methylation on K9 and K27 of histone H3 (H3K9me3 & H3K27me3) are generally
associated with transcriptional repression.
• For many years , histone methylation was thought to be irreversible as it is a stable mark
propagated through multiple cell divisions . However , it was recently shown that ,
similarly to histone acetylation,methylation is an actively regulated and reversible process.

14. The “histone code” regulates gene expression

15. Histone phosphorylation (H3)
• Histones are phosphorylated during mitosis.
• Histones are also phosphorylated by signal transduction pathways
like the ERK pathway in response to external signals .It is not
known how(and if) this phosphorylation contributes to gene
expression.
• Phosphatases remove phosphate groups from histones.

16. Histone ubiquitylation
• Ubiquitin is usually, but not always, attached to proteins as a signal for Degradation by the
proteasome.
• Like other proteins, histones are ubiquitinated through attachment of ubiquitin to the ε -NH+
group of a lysine.
• Ubiquitination of histones H 2 A, H 2 B, H 3 and H 1 has been observed.
• Most histones appear to be mono ubiquitinated although there is evidence for poly
ubiquitination
• Addition and removal of Ub (a LARGE moiety) to histone tails Functions largely unknown in
vertebrates.
• ubiquitylation
• H2 A K 119 : repression
• H2 B K 120 : activation
• H3 and H 4 : DNA repair

17. • DNA methylation
• DNA methylation targets the promoter region of the genes . Promoter contain
are as with a high number of C (cytosine) and G(guanine) DNA bases.
• The cytosine , or C , residues in these areas can have methyl groups added
to them and when this occurs the genes are effectively switched off.
• The methyl groups basically block other proteins from binding to the promoter
region and the gene sequence can not be read.

18. DNA methylation
• Methylation on cytosineson CpG islands.
• In most eukaryotes (except D.melanogaster, C.elegans, few in yeast).
• Methyl group in DNA large furrow.
• No disruption of hydrogen bonds.

19. DNA methylation
• Covalent addition of methyl group to 5 th position of cytosine with CpG
di nucleotides located in the promoter region of genes.

20. DNA methyltransferases

21. • Schematic diagram of the four archetypes of lncRNA mechanism.
• I: As Signals , lncRNA expression can faithfully reflect the combinatorial actions of
transcription factors (coloredovals) or signaling pathways to indicate gene regulation in
space and time.
• II: As Decoys , lncRNAs can titrate away transcription factors and other proteins away
from chromatin , or titrate the protein factors in to nuclear subdomains . A further
example of decoys is lncRNA decoy for miRNA target sites (notshownonschematic).
• III: As Guides , lncRNAs can recruit chromatin modifying enzymes to target genes, either
in cis(near the site of lncRNA production ) or in trans to distant target genes.
• IV: As scaffolds , lncRNAs can bring to gether multiple proteins to form
ribonucleoprotein complexes.The lncRNA- RNP may act on chromatin as illustrated to
affect histone modifications . In other instances , the lncRNA scaffold is structural and
stabilizes nuclear structures or signaling complexes.
• Noncoding RNA

22. • Noncoding RNA

23. Epigenetic-related Events

24. 1. X Inactivation
• Females silence one of their two X-chromosomes through a process referred to as X-
chromosome inactivation , to compensate gene dosage disparities.
• Embryos containing more than one X-chromosome (XX, XXX females and XXY males)
undergo random X-chromosome inactivation at the blastocyst stage in early
embryogenesis.
• It is initiated from XIC (X inactivation Centre ) containing several genes of which two,
i.e XIST & TSIX , play an important role.

25. • X Inactivation

26. 2. Imprinting
• An epigenetic form of gene regulation that results in only the copy
inherited from father or mother to function.
• The first description of the imprinting phenomenon was given by
McGrath and Solter in 1984
• Imprinted genes represent less than 1% of the mammalian genome.
• Igf2 (Paternally expressed) is the first imprinted gene that was
identified in mouse.

27. • Imprinting
• All of us inherit two copies of a gene-one copy from mother and another
one from father. Normally, both copies are active, whereas in some
situations only one of them is turned on. Of these, some genes are active
only when they are inherited from father, while others will be activated
when inherited from mother. So which copy will remain active depends on
their parental origin. These genes are called “imprinted genes.”
• Silencing usually happens through the addition of methyl groups during
egg or sperm formation.
• The epigenetic tags on imprinted genes usually stay put for the life of the
organism. . But they are reset during egg and sperm formation.
Regardless of whether they came from mom or dad, certain genes are
always silenced in the egg, and others are always silenced in the sperm.
• Most imprinted genes are developmental genes which affect fetal growth,
nutrient transfer through placenta, cell proliferation, and brain
development. Usually growth-related genes are maternally imprinted.

28. • Genomic Imprinting
• As an epigenetic process, genomic imprinting alters gene expression without
altering DNA sequence.
• Imprinting control regions (ICRs) are often composed of repetitive DNA sequences
found flanking, or internal to, imprinted genes, and in most cases, removal of an ICR
will result in a loss of imprinting.
• ICRs act as nucleation sites for gene silencing or activation and are able to regulate
expression of a single gene or an entire gene cluster.

29. Imprinted genes are crucial for normal development
• Roles in
– Growth
– Behavior
– Stem cells
– Disease
• Genomic Imprinting